Methods for administering angiotensin II

ABSTRACT

The present disclosure relates to the use of angiotensin II, angiotensin III, or angiotensin IV in therapeutic methods for the treatment of hypotension, especially catecholamine-resistant hypotension.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application Ser. No. 62/276,171, filed Jan. 7, 2016, and U.S.Provisional Patent Application Ser. No. 62/347,292, filed on Jun. 8,2016, each of which are herein incorporated by reference in theirentireties.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Feb. 27, 2017, isnamed LJH-02101_SL.txt and is 4,235 bytes in size.

BACKGROUND OF THE INVENTION

Hypotension, if uncorrected, is life-threatening and occurs as theresult of various underlying conditions such as trauma, septic shock ordrug reactions. The first line of treatment is intravenous fluids, andif this fails to correct the hypotension then vasopressors are deployed.The first line vasopressor is a catecholamine infusion. Catecholaminesare amines derived from the amino acid tyrosine, and they includeepinephrine (adrenaline), norepinephrine (noradrenaline), phenylephrine,and dopamine, which act as both hormones and neurotransmitters thatincrease blood pressure. While largely effective at treatinghypotension, some patients fail to respond to adequate doses and aredefined as catecholamine-resistant. These patients frequently have ahigh mortality and no acceptable alternatives.

The use of high doses of catecholamines in patients with severehypotension is associated with poor outcomes. For example, thein-patient, 90-day mortality rate is 50-93% for patients who requirenorepinephrine as a vasopressor at doses that exceed 0.1 μg/kg/min, and94% of patients who require norepinephrine at doses above 100 μg/mindie.

Thus, alternate methods of regulating blood pressure in patients withcatecholamine-resistant hypotension are needed.

SUMMARY OF THE INVENTION

Angiotensin II is a peptide hormone naturally produced by the body thatregulates blood pressure via vasoconstriction and sodium reabsorption.The hemodynamic effects of angiotensin II administration have been thesubject of numerous clinical studies, demonstrating significant effectson systemic and renal blood flow. The invention disclosed herein relatesto methods of treating hypotension by administering angiotensin II,angiotensin III, or angiotensin IV to a patient.

Various aspects of the invention relate to the finding that somehypotensive patients display a more dramatic response to angiotensin IItherapy than other hypotensive patients. Patients who display a dramaticresponse to angiotensin II may be deficient in angiotensin II, e.g.,because one of the upstream mediators of angiotensin II is deficient. Incontrast, hypotensive patients who are not deficient in angiotensin IImay be relatively less sensitive to angiotensin II. Thus, the componentsof the pathway upstream of angiotensin II may be monitored prior toadministering angiotensin II to a patient to determine an appropriatedose for the patient. For example, a high serum concentration ofangiotensin I in a patient may indicate that the patient is notefficiently converting angiotensin I to angiotensin II, which mayindicate that the patient will be acutely sensitive to subsequentangiotensin II therapy. Similarly, a patient with a low serumconcentration of angiotensin II, or a high angiotensin I to angiotensinII ratio, may be acutely sensitive to angiotensin II therapy.Angiotensin I is converted to angiotensin II by angiotensin convertingenzyme (ACE), which is located predominantly in the lung. Thus, patientswith impaired lung function, such as patients with acute respiratorydistress syndrome, may have lower endogenous angiotensin II production,and such patients may be particularly sensitive to angiotensin IItherapy. Lower doses of angiotensin II therapy may be administered tohypotensive patients who are predicted to be sensitive to angiotensin IItherapy relative to other hypotensive patients, e.g., to inhibit orprevent undesired side effects of exogenous angiotensin II, such ashypertension.

In some aspects, the invention relates to methods of treatinghypotension, such as catecholamine-resistant hypotension, in a patientin need thereof, comprising administering to the patient a compositioncomprising angiotensin II, angiotensin III, or angiotensin IV. The term“catecholamine-resistant hypotension” as used herein refers to patientswho require more than 15 μg/kg/min of dopamine, 0.1 μg/kg/minnorepinephrine, or 0.1 μg/kg/min epinephrine as a vasopressor. Dopamine,norepinephrine, and epinephrine may be administered at rates higher than15 μg/kg/min, 0.1 μg/kg/min, or 0.1 μg/kg/min, respectively, butelevated rates correlate with increased mortality.

In some embodiments, the invention relates to a method of treatinghypotension in a human patient, comprising measuring a feature in thepatient and administering a composition comprising angiotensin II,angiotensin III, or angiotensin IV to the patient. The feature may be,for example, a blood concentration of angiotensin II, a bloodconcentration of angiotensin I, or a ratio of the blood concentration ofangiotensin I to the blood concentration of angiotensin II. The featuremay be blood plasma renin activity, a blood concentration of angiotensinconverting enzyme (ACE), a blood concentration of aldosterone, a bloodconcentration of anti-diuretic hormone (ADH), or a blood concentrationof angiotensinogen. The feature may be lung function.

In some embodiments, the invention relates to a method of diagnosingacute respiratory distress syndrome (ARDS) in a human patient,comprising measuring a feature in the patient. The feature may be, forexample, a blood concentration of angiotensin II, a blood concentrationof angiotensin I, or a ratio of the blood concentration of angiotensin Ito the blood concentration of angiotensin II. The feature may be a bloodconcentration of angiotensin converting enzyme (ACE) or a bloodconcentration of angiotensinogen.

In some embodiments, the invention relates to a method of diagnosingcatecholamine-resistant hypotension (CRH) in a human patient, comprisingmeasuring a feature in the patient. The feature may be, for example, ablood concentration of angiotensin II, a blood concentration ofangiotensin I, or a ratio of the blood concentration of angiotensin I tothe blood concentration of angiotensin II. The feature may be bloodplasma renin activity, a blood concentration of angiotensin convertingenzyme (ACE), a blood concentration of aldosterone, a bloodconcentration of anti-diuretic hormone (ADH), or a blood concentrationof angiotensinogen. The feature may be lung function.

The method may comprise administering angiotensin II (or angiotensin IIIor angiotensin IV) at a first rate if a measurement is greater than athreshold value. The method may comprise administering angiotensin II(or angiotensin III or angiotensin IV) at a first rate if themeasurement is greater than or equal to a threshold value (i.e., if themeasurement is at least a threshold value). The method may compriseadministering angiotensin II (or angiotensin III or angiotensin IV) at asecond rate if the measurement is less than a threshold value. Themethod may comprise administering angiotensin II (or angiotensin III orangiotensin IV) at a second rate if the measurement is less than orequal to a threshold value. The first rate and/or second rate may be theinitial rate at which angiotensin II (or angiotensin III or angiotensinIV) is administered to the patient.

The method may comprise administering angiotensin II (or angiotensin IIIor angiotensin IV) at a first rate if the measurement is less than athreshold value. The method may comprise administering angiotensin II(or angiotensin III or angiotensin IV) at a first rate if themeasurement is less than or equal to a threshold value. The method maycomprise administering angiotensin II (or angiotensin III or angiotensinIV) at a second rate if a measurement is greater than a threshold value.The method may comprise administering angiotensin II (or angiotensin IIIor angiotensin IV) at a second rate if the measurement is greater thanor equal to a threshold value (i.e., if the measurement is at least athreshold value). The first rate and/or second rate may be the initialrate at which angiotensin II (or angiotensin III or angiotensin IV) isadministered to the patient.

The measurement may be a measurement of a blood concentration ofangiotensin II, a blood concentration of angiotensin I, or a ratio ofthe blood concentration of angiotensin I to the blood concentration ofangiotensin II. The measurement may be a measurement of blood plasmarenin activity, a blood concentration of angiotensin converting enzyme(ACE), a blood concentration of aldosterone, a blood concentration ofanti-diuretic hormone (ADH), or a blood concentration ofangiotensinogen. The measurement may be a measurement of lung function.

In some embodiments, the invention relates to a method of treatinghypotension in a human patient, comprising determining whether thepatient has acute respiratory distress syndrome and administering acomposition comprising angiotensin II (or angiotensin III or angiotensinIV) to the patient. The method may comprise administering angiotensin II(or angiotensin III or angiotensin IV) at a first rate if the patienthas acute respiratory distress syndrome. The method may compriseadministering angiotensin II (or angiotensin III or angiotensin IV) at asecond rate if the patient does not have acute respiratory distresssyndrome. The first rate and/or second rate may be the initial rate atwhich angiotensin II (or angiotensin III or angiotensin IV) isadministered to the patient.

In some embodiments, the invention relates to a method of treatinghypotension in a human patient, comprising determining whether thepatient received an angiotensin converting enzyme inhibitor (ACEinhibitor) within a preceding period of time and administering acomposition comprising angiotensin II (or angiotensin III or angiotensinIV) to the patient. The method may comprise administering angiotensin II(or angiotensin III or angiotensin IV) at a first rate if the patientreceived an ACE inhibitor within the preceding period of time. Themethod may comprise administering angiotensin II (or angiotensin III orangiotensin IV) at a second rate if the patient did not receive an ACEinhibitor within the preceding period of time. The ACE inhibitor may be,for example, perindopril, captopril, enalapril, lisinopril, benazepril,fosinopril, moexipril, quinapril, trandolapril, or ramipril. Thepreceding period of time may be, for example, about 1 hour, about 2hours, about 3, hours, about 4 hours, about 5 hours, about 6 hours,about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours,about 20 hours, about 24 hours, about 30 hours, about 36 hours, about 48hours, or about 72 hours. The preceding period of time may be about 1day, about 2 days, about 3 days, about 4 days, about 5 days, about 6days, or about 7 days. The preceding period of time may be about 1 hourto about 7 days, about 1 hour to about 72 hours, about 1 hour to about48 hours, about 1 hour to about 24 hours, about 1 hour to about 12hours, or about 1 day to about 7 days. The first rate and/or second ratemay be the initial rate at which angiotensin II (or angiotensin III orangiotensin IV) is administered to the patient.

The first rate may be, for example, at least 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50ng/kg/min angiotensin II (or angiotensin III or angiotensin IV). Thefirst rate may be greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 ng/kg/minangiotensin II (or angiotensin III or angiotensin IV). The first ratemay be less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 ng/kg/min angiotensin II (orangiotensin III or angiotensin IV). The first rate may be less than orequal to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 25, 30, 35, 40, 45, or 50 ng/kg/min angiotensin II (orangiotensin III or angiotensin IV). The first rate may be about 1, about2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about10, about 11,about 12, about 13, about 14, about 15, about 16, about 17,about 18, about 19, about 20, about 25, about 30, about 35, about 40,about 45, or about 50 ng/kg/min angiotensin II (or angiotensin III orangiotensin IV). The first rate may be about 0.1 ng/kg/min to 20ng/kg/min, about 0.1 ng/kg/min to about 19 ng/kg/min, about 0.1ng/kg/min to about 18 ng/kg/min, about 0.1 ng/kg/min to about 17.5ng/kg/min, about 0.2 ng/kg/min to about 17.5 ng/kg/min, about 0.25ng/kg/min to about 17.5 ng/kg/min, about 0.1 ng/kg/min to about 15ng/kg/min, about 0.2 ng/kg/min to about 15 ng/kg/min, or about 0.25ng/kg/min to about 15 ng/kg/min. The first rate may be about 0.5ng/kg/min to 20 ng/kg/min, about 0.5 ng/kg/min to about 19 ng/kg/min,about 0.5 ng/kg/min to about 18 ng/kg/min, about 0.5 ng/kg/min to about17.5 ng/kg/min, about 0.75 ng/kg/min to about 17.5 ng/kg/min, about 1.0ng/kg/min to about 17.5 ng/kg/min, about 0.5 ng/kg/min to about 15ng/kg/min, about 0.75 ng/kg/min to about 15 ng/kg/min, or about 1.0ng/kg/min to about 15 ng/kg/min. The first rate may be 20 ng/kg/min toabout 200 ng/kg/min, 20 ng/kg/min to about 120 ng/kg/min, 20 ng/kg/minto about 100 ng/kg/min, 20 ng/kg/min to about 90 ng/kg/min, 20 ng/kg/minto about 80 ng/kg/min, 20 ng/kg/min to about 70 ng/kg/min, 20 ng/kg/minto about 60 ng/kg/min, or 20 ng/kg/min to about 50 ng/kg/min.

The second rate may be, for example, at least 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 85, 90, 95, or 100 ng/kg/min angiotensin II (or angiotensin IIIor angiotensin IV). The second rate may be greater than 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40,45, or 50 ng/kg/min angiotensin II (or angiotensin III or angiotensinIV). The second rate may be less than 20, 25, 30, 35, 40, 45, 50, 55,60, 65, 70, 75, 80, 85, 90, 95, or 100 ng/kg/min angiotensin II (orangiotensin III or angiotensin IV). The second rate may be less than orequal to 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,or 100 ng/kg/min angiotensin II (or angiotensin III or angiotensin IV).The second rate may be about 1, about 2, about 3, about 4, about 5,about 6, about 7, about 8, about 9, about 10, about 11, about 12, about13, about 14, about 15, about 16, about 17, about 18, about 19, about20, about 25, about 30, about 35, about 40, about 45, about 50, about55, about 60, about 65, about 70, about 75, about 80, about 85, about90, about 95, about or 100 ng/kg/min angiotensin II (or angiotensin IIIor angiotensin IV). The second rate may be about 0.1 ng/kg/min to 20ng/kg/min, about 0.1 ng/kg/min to about 19 ng/kg/min, about 0.1ng/kg/min to about 18 ng/kg/min, about 0.1 ng/kg/min to about 17.5ng/kg/min, about 0.2 ng/kg/min to about 17.5 ng/kg/min, about 0.25ng/kg/min to about 17.5 ng/kg/min, about 0.1 ng/kg/min to about 15ng/kg/min, about 0.2 ng/kg/min to about 15 ng/kg/min, or about 0.25ng/kg/min to about 15 ng/kg/min. The second rate may be about 0.5ng/kg/min to 20 ng/kg/min, about 0.5 ng/kg/min to about 19 ng/kg/min,about 0.5 ng/kg/min to about 18 ng/kg/min, about 0.5 ng/kg/min to about17.5 ng/kg/min, about 0.75 ng/kg/min to about 17.5 ng/kg/min, about 1.0ng/kg/min to about 17.5 ng/kg/min, about 0.5 ng/kg/min to about 15ng/kg/min, about 0.75 ng/kg/min to about 15 ng/kg/min, or about 1.0ng/kg/min to about 15 ng/kg/min. The second rate may be 20 ng/kg/min toabout 200 ng/kg/min, 20 ng/kg/min to about 120 ng/kg/min, 20 ng/kg/minto about 100 ng/kg/min, 20 ng/kg/min to about 90 ng/kg/min, 20 ng/kg/minto about 80 ng/kg/min, 20 ng/kg/min to about 70 ng/kg/min, 20 ng/kg/minto about 60 ng/kg/min, or 20 ng/kg/min to about 50 ng/kg/min.

The feature may be a blood concentration of angiotensin II, and thethreshold may be 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,80, 85, 90, 95, or 100 ng/mL. The method may comprise administeringangiotensin II (or angiotensin III or angiotensin IV) at a first rate ifthe measured blood concentration of angiotensin II is less than (or lessthan or equal to) the threshold. The method may comprise administeringangiotensin II (or angiotensin III or angiotensin IV) at a second rateif the measured blood concentration of angiotensin II is greater than(or greater than or equal to) the threshold. For example, the method maycomprise administering angiotensin II at an initial rate of less than orequal to 20 ng/kg/min if the blood concentration of angiotensin II isless than or equal to 50 ng/mL. Similarly, the method may compriseadministering angiotensin II at an initial rate of greater than or equalto 20 ng/kg/min if the blood concentration of angiotensin II is greaterthan 50 ng/mL. The method may comprise administering angiotensin II atan initial rate of less than 20 ng/kg/min if the blood concentration ofangiotensin II is less than or equal to 50 ng/mL (or less than or equalto a different threshold). The method may comprise administeringangiotensin II at an initial rate of greater than or equal to 20ng/kg/min if the blood concentration of angiotensin II is greater than50 ng/mL (or greater than a different threshold). The method maycomprise diagnosing the patient with acute respiratory distress syndromeif the measured blood concentration of angiotensin II is less than (orless than or equal to) the threshold (e.g., less than 20 ng/kg/min). Themethod may comprise diagnosing the patient with catecholamine-resistanthypotension if the measured blood concentration of angiotensin II isless than (or less than or equal to) the threshold (e.g., less than 20ng/kg/min).

The feature may be a blood concentration of angiotensin I, and thethreshold may be 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600,650, 700, 750, 800, 850, 900, 950, or 1000 pg/mL. The method maycomprise administering angiotensin II (or angiotensin III or angiotensinIV) at a first rate if the measured blood concentration of angiotensin Iis greater than (or greater than or equal to) the threshold. The methodmay comprise administering angiotensin II (or angiotensin III orangiotensin IV) at a second rate if the measured blood concentration ofangiotensin I is less than (or less than or equal to) the threshold. Forexample, the method may comprise administering angiotensin II at aninitial rate of less than or equal to 20 ng/kg/min if the bloodconcentration of angiotensin I is at least 500 pg/mL. Similarly, themethod may comprise administering angiotensin II at an initial rate ofgreater than or equal to 20 ng/kg/min if the blood concentration ofangiotensin I is less than 500 pg/mL. The method may compriseadministering angiotensin II at an initial rate of less than 20ng/kg/min if the blood concentration of angiotensin I is at least 500pg/mL (or at least a different threshold). Similarly, the method maycomprise administering angiotensin II at an initial rate of greater thanor equal to 20 ng/kg/min if the blood concentration of angiotensin I isless than 500 pg/mL (or less than a different threshold). The method maycomprise diagnosing the patient with acute respiratory distress syndromeif the measured blood concentration of angiotensin I is greater than (orgreater than or equal to) the threshold (e.g., greater than 500 pg/mL).The method may comprise diagnosing the patient withcatecholamine-resistant hypotension if the measured blood concentrationof angiotensin I is greater than (or greater than or equal to) thethreshold (e.g., greater than 500 pg/mL).

The feature may be a ratio of the blood concentration of angiotensin Iand the blood concentration of angiotensin II, and the threshold may be1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1:9,1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1,8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, or20:1. The method may comprise administering angiotensin II (orangiotensin III or angiotensin IV) at a first rate if the measured ratiois greater than (or greater than or equal to) the threshold. The methodmay comprise administering angiotensin II (or angiotensin III orangiotensin IV) at a second rate if the measured ratio is less than (orless than or equal to) the threshold. For example, the method maycomprise administering angiotensin II at an initial rate of less than orequal to 20 ng/kg/min if the ratio of angiotensin I to angiotensin II isat least 1:1. Similarly, the method may comprise administeringangiotensin II at an initial rate of greater than or equal to 20ng/kg/min if the ratio of angiotensin I to angiotensin II is less than1:1. The method may comprise administering angiotensin II at an initialrate of less than 20 ng/kg/min if the ratio of angiotensin I toangiotensin II is at least 1:1 (or at least a different threshold). Themethod may comprise administering angiotensin II at an initial rate ofgreater than or equal to 20 ng/kg/min if the ratio of angiotensin I toangiotensin II is less than 1:1 (or less than a different threshold).The method may comprise diagnosing the patient with acute respiratorydistress syndrome if the ratio of angiotensin I to angiotensin II isgreater than (or greater than or equal to) the threshold (e.g., greaterthan 1:1). The method may comprise diagnosing the patient withcatecholamine-resistant hypotension if the ratio of angiotensin I toangiotensin II is greater than (or greater than or equal to) thethreshold (e.g., greater than 1:1).

The feature may be blood plasma renin activity, and the threshold may be5.0, 4.0, 3.0, 2.0, 1.5, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4,0.3, 0.2, or 0.1 μIU/mL. The method may comprise administeringangiotensin II (or angiotensin III or angiotensin IV) at a first rate ifthe measured blood plasma renin activity is less than (or less than orequal to) the threshold. The method may comprise administeringangiotensin II (or angiotensin III or angiotensin IV) at a second rateif the measured blood plasma renin activity is greater than (or greaterthan or equal to) the threshold. For example, the method may compriseadministering angiotensin II at an initial rate of less than or equal to20 ng/kg/min if the blood plasma renin activity is less than 1.2 μIU/mL.Similarly, the method may comprise administering angiotensin II at aninitial rate of greater than or equal to 20 ng/kg/min if the bloodconcentration of blood plasma renin activity is at least 1.2 μIU/mL. Themethod may comprise administering angiotensin II at an initial rate ofless than 20 ng/kg/min if the blood plasma renin activity is less than1.2 μIU/mL (or less than a different threshold). The method may compriseadministering angiotensin II at an initial rate of greater than or equalto 20 ng/kg/min if the blood concentration of blood plasma reninactivity is at least 1.2 μIU/mL (or greater than or equal to a differentthreshold). The method may comprise diagnosing the patient withcatecholamine-resistant hypotension if the blood plasma renin activityis less than (or less than or equal to) the threshold (e.g., less than1.2 μIU/mL).

The feature may be a blood concentration of angiotensin convertingenzyme (ACE), and the threshold may be 5, 10, 15, 20, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 nmol/mL. The methodmay comprise administering angiotensin II (or angiotensin III orangiotensin IV) at a first rate if the measured blood concentration ofACE is less than (or less than or equal to) the threshold. The methodmay comprise administering angiotensin II (or angiotensin III orangiotensin IV) at a second rate if the measured blood concentration ofACE is greater than (or greater than or equal to) the threshold. Forexample, the method may comprise administering angiotensin II at aninitial rate of less than or equal to 20 ng/kg/min if the bloodconcentration of ACE is less than 40 nmol/mL. Similarly, the method maycomprise administering angiotensin II at an initial rate of greater thanor equal to 20 ng/kg/min if the blood concentration of ACE is at least40 nmol/mL. The method may comprise administering angiotensin II at aninitial rate of less than 20 ng/kg/min if the blood concentration of ACEis less than 40 nmol/mL (or less than a different threshold). The methodmay comprise administering angiotensin II at an initial rate of greaterthan or equal to 20 ng/kg/min if the blood concentration of ACE is atleast 40 nmol/mL (or greater than or equal to a different threshold).The method may comprise diagnosing the patient with acute respiratorydistress syndrome if the blood concentration of ACE is less than (orless than or equal to) the threshold (e.g., less than 40 nmol/mL). Themethod may comprise diagnosing the patient with catecholamine-resistanthypotension if the blood concentration of ACE is less than (or less thanor equal to) the threshold (e.g., less than 40 nmol/mL).

The feature may be a blood concentration of aldosterone, and thethreshold may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20 ng/dL. The method may comprise administeringangiotensin II (or angiotensin III or angiotensin IV) at a first rate ifthe measured blood concentration of aldosterone is less than (or lessthan or equal to) the threshold. The method may comprise administeringangiotensin II (or angiotensin III or angiotensin IV) at a second rateif the measured blood concentration of aldosterone is greater than (orgreater than or equal to) the threshold. For example, the method maycomprise administering angiotensin II at an initial rate of less than orequal to 20 ng/kg/min if the blood concentration of aldosterone is lessthan 5 ng/dL. Similarly, the method may comprise administeringangiotensin II at an initial rate of greater than or equal to 20ng/kg/min if the blood concentration of aldosterone is at least 5 ng/dL.The method may comprise administering angiotensin II at an initial rateof less than 20 ng/kg/min if the blood concentration of aldosterone isless than 5 ng/dL (or less than a different threshold). The method maycomprise administering angiotensin II at an initial rate of greater thanor equal to 20 ng/kg/min if the blood concentration of aldosterone is atleast 5 ng/dL (or greater than or equal to a different threshold). Themethod may comprise diagnosing the patient with catecholamine-resistanthypotension if the blood concentration of aldosterone is less than (orless than or equal to) the threshold (e.g., less than 5 ng/dL).

The feature may be a blood concentration of anti-diuretic hormone (ADH),and the threshold may be 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5,5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, or 10.5 pg/mL.The method may comprise administering angiotensin II (or angiotensin IIIor angiotensin IV) at a first rate if the measured blood concentrationof ADH is less than (or less than or equal to) the threshold. The methodmay comprise administering angiotensin II (or angiotensin III orangiotensin IV) at a second rate if the measured blood concentration ofADH is greater than (or greater than or equal to) the threshold. Forexample, the method may comprise administering angiotensin II at aninitial rate of less than or equal to 20 ng/kg/min if the bloodconcentration of ADH is less than 2.5 pg/mL. Similarly, the method maycomprise administering angiotensin II at an initial rate of greater thanor equal to 20 ng/kg/min if the blood concentration of ADH is at least2.5 pg/ml. The method may comprise administering angiotensin II at aninitial rate of less than 20 ng/kg/min if the blood concentration of ADHis less than 2.5 pg/mL (or less than a different threshold). The methodmay comprise administering angiotensin II at an initial rate of greaterthan or equal to 20 ng/kg/min if the blood concentration of ADH is atleast 2.5 pg/ml (or at least a different threshold). The method maycomprise diagnosing the patient with catecholamine-resistant hypotensionif the blood concentration of ADH is less than (or less than or equalto) the threshold (e.g., less than 2.5 pg/ml).

The feature may be a blood concentration of angiotensinogen, and thethreshold may be 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550,600, 650, 700, 750, 800, 850, 900, or 950 ng/mL. The method may compriseadministering angiotensin II (or angiotensin III or angiotensin IV) at afirst rate if the measured blood concentration of angiotensinogen isgreater than (or greater than or equal to) the threshold. The method maycomprise administering angiotensin II (or angiotensin III or angiotensinIV) at a second rate if the measured blood concentration ofangiotensinogen is less than (or less than or equal to) the threshold.For example, the method may comprise administering angiotensin II at aninitial rate of less than or equal to 20 ng/kg/min if the bloodconcentration of angiotensinogen is at least 250 ng/mL. Similarly, themethod may comprise administering angiotensin II at an initial rate ofgreater than or equal to 20 ng/kg/min if the blood concentration ofangiotensinogen is less than or equal to 250 ng/mL. The method maycomprise administering angiotensin II at an initial rate of less than 20ng/kg/min if the blood concentration of angiotensinogen is at least 250ng/mL (or greater than or equal to a different threshold). The methodmay comprise administering angiotensin II at an initial rate of greaterthan or equal to 20 ng/kg/min if the blood concentration ofangiotensinogen is less than 250 ng/mL (or less than a differentthreshold). The method may comprise diagnosing the patient with acuterespiratory distress syndrome if the blood concentration ofangiotensinogen is greater than (or greater than or equal to) thethreshold (e.g., greater than 250 ng/mL). The method may comprisediagnosing the patient with catecholamine-resistant hypotension if theblood concentration of angiotensinogen is greater than (or greater thanor equal to) the threshold (e.g., greater than 250 ng/mL).

The feature may be lung function, and the method may compriseadministering angiotensin II (or angiotensin III or angiotensin IV) tothe patient at a first rate if the patient has impaired lung function.The feature may be lung function, and the method may compriseadministering angiotensin II (or angiotensin III or angiotensin IV) tothe patient at a second rate if the patient does not have impaired lungfunction. For example, the method may comprise administering angiotensinII at an initial rate of less than or equal to 20 ng/kg/min if thepatient has impaired lung function. Similarly, the method may compriseadministering angiotensin II at an initial rate of greater than or equalto 20 ng/kg/min if the patient does not have impaired lung function. Themethod may comprise administering angiotensin II at an initial rate ofless than 20 ng/kg/min if the patient has impaired lung function.

Impaired lung function may be an acute or chronic lung conditionselected from a respiratory disease, an inflammatory lung disease, arespiratory tract infection, a restrictive lung disease, lung cancer, apleural cavity disease, a pulmonary vascular disease (such as apulmonary embolism), acute respiratory distress syndrome, or lungtrauma. “Measuring” lung function may include diagnosing the patientwith an acute or chronic lung condition, or obtaining informationrelated to lung function, such as by consulting a care provider of thepatient, consulting a family member or an emergency contact of thepatient, or by reviewing the medical history of the patient. Forexample, “measuring lung function” may comprise reviewing a medicalrecord of a patient.

The method may comprise determining whether the patient has acuterespiratory distress syndrome and administering a composition comprisingangiotensin II (or angiotensin III or angiotensin IV) to the patient ata first rate if the patient has acute respiratory distress syndrome. Themethod may comprise determining whether the patient has acuterespiratory distress syndrome and administering a composition comprisingangiotensin II (or angiotensin III or angiotensin IV) to the patient ata second rate if the patient does not have acute respiratory distresssyndrome. For example, the method may comprise administering angiotensinII at an initial rate of less than or equal to 20 ng/kg/min if thepatient has acute respiratory distress syndrome. Similarly, the methodmay comprise administering angiotensin II at an initial rate of greaterthan or equal to 20 ng/kg/min if the patient does not have acuterespiratory distress syndrome. The method may comprise administeringangiotensin II at an initial rate of less than 20 ng/kg/min if thepatient has acute respiratory distress syndrome.

The method may comprise determining whether the patient received anangiotensin converting enzyme inhibitor (ACE inhibitor) within apreceding period of time and administering a composition comprisingangiotensin II (or angiotensin III or angiotensin IV) to the patient ata first rate if the patient received an ACE inhibitor within thepreceding period of time. The method may comprise determining whetherthe patient received an angiotensin converting enzyme inhibitor (ACEinhibitor) within a preceding period of time and administering acomposition comprising angiotensin II (or angiotensin III or angiotensinIV) to the patient at a second rate if the patient has not received anACE inhibitor within the preceding period of time. For example, themethod may comprise determining whether the patient received an ACEinhibitor within a preceding period of time (e.g., within 24 hours) andadministering angiotensin II to the patient at an initial rate of lessthan or equal to 20 ng/kg/min if the patient received an ACE inhibitorwithin the preceding period of time. Similarly, the method may comprisedetermining whether the patient received an ACE inhibitor within apreceding period of time (e.g., within 24 hours) and administeringangiotensin II to the patient at an initial rate of greater than orequal to 20 ng/kg/min if the patient did not receive an ACE inhibitorwithin the preceding period of time. The method may comprise determiningwhether the patient received an ACE inhibitor within a preceding periodof time (e.g., within 24 hours) and administering angiotensin II to thepatient at an initial rate of less than 20 ng/kg/min if the patientreceived an ACE inhibitor within the preceding period of time.

In some embodiments, the patient is receiving a vasopressor, i.e., otherthan the angiotensin II, angiotensin III, or angiotensin IV. The methodmay comprise decreasing the rate at which the vasopressor isadministered.

The method may comprise measuring a mean arterial pressure (MAP) of thepatient a subsequent period of time after administering to the patientthe composition comprising angiotensin II (or angiotensin III orangiotensin IV). The term “mean arterial pressure” or “MAP” refers tothe average arterial pressure during a single cardiac cycle. The methodmay comprise decreasing the rate at which a vasopressor is administered(i.e., a vasopressor other than the angiotensin II, angiotensin III, orangiotensin IV), if the measured mean arterial pressure is at or above50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or85 mm Hg (referred to as a target value or target MAP herein). Forexample, the method may comprise decreasing the rate at which avasopressor is administered if the measured mean arterial pressure is ator above 75 mm Hg. The method may further comprise increasing the rateat which the angiotensin II (or angiotensin III or angiotensin IV) isadministered if the measured mean arterial pressure is less than 75 mmHg (or less than 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, or 85 mm Hg, e.g., wherein the target MAP corresponds to thetarget MAP for decreasing the rate at which the vasopressor isadministered).

A patient may have a known initial mean arterial pressure prior toadministering the composition comprising angiotensin II, angiotensinIII, or angiotensin IV (referred to as an initial mean arterial pressureherein, which is distinguished from a measured mean arterial pressurethat is obtained after administering the composition to the patient).For example, the method may comprise measuring a mean arterial pressureprior to administering the composition to the patient. The method maycomprise decreasing the rate at which a vasopressor is administered(i.e., a vasopressor other than the angiotensin II, angiotensin III, orangiotensin IV), if the measured mean arterial pressure (obtained asubsequent period of time after administering to the patient thecomposition) is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 20 mm Hg higher than the initial mean arterialpressure. For example, the method may comprise decreasing the rate atwhich a vasopressor is administered if the measured mean arterialpressure is at least 10 mm Hg higher than the initial mean arterialpressure. The method may further comprise increasing the rate at whichthe angiotensin II (or angiotensin III or angiotensin IV) isadministered if the measured mean arterial pressure is less than 10 mmHg higher than the initial mean arterial pressure (or less than 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mm Hghigher than the initial mean arterial pressure, e.g., wherein thethreshold difference between the measured and initial MAP corresponds tothe threshold difference for decreasing the rate at which thevasopressor is administered).

Those of skill in the art will recognize that in the context of thepresent invention, anti-hypotensive therapeutics can be administered inany suitable way, but are typically administered by continuous infusion.Accordingly, increasing or decreasing a rate of administration can beaccomplished by changing the rate of flow of an intravenous drip,changing the concentration of the agent in an intravenous drip, etc.However, the manner in which the rate of administration is changed willdepend on the mode of administration of the therapeutic. Where thetherapeutic is administered transmucosally or transdermally, the ratemay be increased by changing to a higher-release-rate patch ortransdermal composition for example. Where the therapeutic isadministered orally, the rate may be increased by switching to ahigher-dose form, administering additional doses, or administeringcontrolled-release dosage forms with a higher rate of release, forexample. Where the therapeutic is administered by inhalation, the ratemay be increased by administering additional boluses, a moreconcentrated bolus, or a faster-release bolus, for example. Other modesof administration (via subcutaneous injection pump, suppository, etc.)can be modulated in analogous fashions, and decreasing the rate ofadministration can be accomplished by doing the opposite of an actionthat would increase the rate of administration of the therapeutic.

Angiotensin II, angiotensin III, and angiotensin IV may be particularlyuseful for patients who require potentially harmful doses ofvasopressors. Thus, in some embodiments, the invention relates tomethods of treating hypotension, wherein, prior to administering thecomposition, the patient is receiving dopamine, dobutamine,norepinephrine, epinephrine, phenylephrine, terlipressin, vasopressin, avasopressin analogue, or midodrine as a vasopressor. The vasopressor maybe, for example, a catecholamine. The term “catecholamine”, as usedherein, refers to dopamine, norepinephrine, phenylephrine, andepinephrine and their prodrugs, structural analogs, or derivatives thatinduce similar physiological effects in humans, e.g., raise meanarterial pressure in healthy human subjects. In certain embodiments, thecatecholamine may be dopamine, norepinephrine, or epinephrine. Thevasopressor may be vasopressin or a vasopressin analogue. A vasopressinanalogue may be, for example, terlipressin, argipressin, desmopressin,felypressin, lypressin, or ornipressin. In some embodiments, a methodcomprises administering two or more of angiotensin II, angiotensin III,angiotensin IV, a catecholamine, vasopressin, a vasopressin analog,dobutamine, and midodrine to a patient. For example, a method maycomprise administering angiotensin II, a catecholamine, and eithervasopressin or a vasopressin analog to a patient. A method may compriseadministering angiotensin II, a catecholamine, and vasopressin to apatient.

In some embodiments, the invention relates to methods of treatinghypotension wherein the patient has a cardiovascular sequential organfailure assessment score (“SOFA score”) of 1 or greater prior toinitiation of angiotensin II therapy (or angiotensin III therapy orangiotensin IV therapy). For example, a patient may have acardiovascular SOFA score of 1, 2, 3, or 4. In some embodiments, thepatient has a cardiovascular SOFA score of 2, 3, or 4. In otherembodiments, the patient has a cardiovascular SOFA score of 3 or 4. Insome embodiments, the patient has a cardiovascular SOFA score of 4 priorto initiation of angiotensin II therapy (or angiotensin III therapy orangiotensin IV therapy).

In some embodiments, the patient is receiving at least 0.1, 0.2, 0.3,0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3,3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, or 5 μg/kg/min of norepinephrine prior to administration ofangiotensin II (or angiotensin III or angiotensin IV). For example,prior to administering the composition, the patient may be receiving atleast 0.1 μg/kg/min of norepinephrine. In some embodiments, the patientmay be receiving at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 μg/min of norepinephrineprior to administering the composition.

Alternatively, hypotension may be treated with epinephrine. Thus, insome embodiments, the patient may be receiving at least 0.1, 0.2, 0.3,0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3,3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, or 5 μg/kg/min of epinephrine prior to initiation of angiotensin IItherapy (or angiotensin III therapy or angiotensin IV therapy). Forexample, prior to administering the composition, the patient may bereceiving at least 0.1 μg/kg/min of epinephrine. In some embodiments,the patient may be receiving at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 μg/min ofepinephrine prior to initiation of angiotensin II therapy (orangiotensin III therapy or angiotensin IV therapy).

Alternatively, hypotension may be treated with dopamine. Thus, in someembodiments, the patient may be receiving at least 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 μg/kg/minof dopamine prior to initiation of angiotensin II therapy (orangiotensin III therapy or angiotensin IV therapy). For example, priorto administering the composition, the patient may be receiving at least5 μg/kg/min of dopamine. In some embodiments, the patient may bereceiving at least 250, 260, 270, 280, 290, 300, 310, 320, 330, 340,350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480,490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620,630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760,770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900,910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1100, 1200, 1300,1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, or2500 μg/min of dopamine prior to initiation of angiotensin II therapy(or angiotensin III therapy or angiotensin IV therapy).

Alternatively, hypotension may be treated with vasopressin. Thus, insome embodiments, the patient may be receiving at least 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,or 25 mU/kg/min vasopressin. In some embodiments, the patient may bereceiving at least 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09,0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.25,0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3,3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5,4.6, 4.7, 4.8, 4.9, or 5.0 U/min vasopressin. For example, prior toadministering the composition, the patient may be receiving at least0.01 U/min of vasopressin.

The patient's mean arterial pressure may be monitored to titrateangiotensin II, angiotensin III, angiotensin IV, or the vasopressor. Forexample, the patient's mean arterial pressure may be monitored with anindwelling arterial line or by other suitable methods. In someembodiments, an initial mean arterial pressure is measured prior toadministering the composition, the composition is administered, and,after a subsequent period of time, an additional mean arterial pressureis measured. The subsequent period of time may be, for example, about 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 135,150, 165, 180, 195, 210, 225, or 240 minutes, or about 4.0, 4.5, 5.0,5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5,12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5,18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, or 48 hours or longer. Preferably, thesubsequent period of time is less than two hours, most preferably aboutone hour or less.

In certain embodiments, if the measured mean arterial pressure meets orexceeds a target value, then the rate at which a vasopressor isadministered is decreased. The target value may be, for example, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,or 80 mm Hg. In certain preferred embodiments, if the measured meanarterial pressure is at or above 75 mm Hg, then the rate at which avasopressor is administered is decreased (i.e., any vasopressor,including angiotensin II, angiotensin III, angiotensin IV, acatecholamine, vasopressin, etc.).

In other embodiments, if the difference between the measured meanarterial pressure and the initial mean arterial pressure meets orexceeds a target value, then the rate at which a vasopressor isadministered is decreased. The target value may be, for example, 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, or 25 mm Hg. In certain preferred embodiments, if the measuredmean arterial pressure is at least 10 mm Hg higher than the initial meanarterial pressure, then the rate at which a vasopressor is administeredis decreased (i.e., any vasopressor, including angiotensin II,angiotensin III, angiotensin IV, a catecholamine, vasopressin, etc.).

The mean arterial pressure may be measured more than once; for example,the mean arterial pressure may be measured 1, 2, 3, 4, 5, 6, 7, 8, 9,10, or more times, or even continuously or substantially continuously.The rate at which a vasopressor is administered may be decreased inresponse to each measurement (i.e., any vasopressor, includingangiotensin II, angiotensin III, angiotensin IV, a catecholamine,vasopressin, etc.), depending on whether the measured mean arterialpressure meets or exceeds a target value. Similarly, the rate at which avasopressor is administered may be increased after a measurement (i.e.,any vasopressor, including angiotensin II, angiotensin III, angiotensinIV, a catecholamine, vasopressin, etc., if the measured mean arterialpressure is less than a target value. Similarly, the rate at which avasopressor is administered may be decreased after each measurement(i.e., any vasopressor, including angiotensin II, angiotensin III,angiotensin IV, a catecholamine, vasopressin, etc.), depending onwhether the difference between the measured mean arterial pressure andthe initial mean arterial pressure is less than a target value.Similarly, the rate at which a vasopressor is administered may beincreased after a measurement (i.e., any vasopressor, includingangiotensin II, angiotensin III, angiotensin IV, a catecholamine,vasopressin, etc.), if the difference between the measured mean arterialpressure and the initial mean arterial pressure is less than a targetvalue.

In some embodiments, if the patient's measured mean arterial pressure isat or above 75 mm Hg, then the rate at which a vasopressor isadministered to the patient is decreased (i.e., any vasopressor,including angiotensin II, angiotensin III, and angiotensin IV). In someembodiments, if the patient's measured mean arterial pressure is at orabove 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, or 85 mm Hg, then the rate at which a vasopressor isadministered to the patient is decreased (i.e., any vasopressor,including angiotensin II, angiotensin III, angiotensin IV, acatecholamine, vasopressin, etc.). In some embodiments, if the measuredmean arterial pressure is at least 10 mm Hg higher than the initial meanarterial pressure, then the rate at which a vasopressor is administeredto the patient is decreased (i.e., any vasopressor, includingangiotensin II, angiotensin III, angiotensin IV, a catecholamine,vasopressin, etc.). In some embodiments, if the measured mean arterialpressure is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mm Hg higher than the initialmean arterial pressure, then the rate at which a vasopressor isadministered to the patient is decreased (i.e., any vasopressor,including angiotensin II, angiotensin III, angiotensin IV, acatecholamine, vasopressin, etc.). In certain embodiments, the rate atwhich a vasopressor is administered is decreased by at least 1%, 2%, 3%,4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%,33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%,47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%,61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%,75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%,99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or more (i.e., avasopressor other than angiotensin II, angiotensin III, or angiotensinIV, e.g., which the patient is receiving prior to administering thecomposition). Thus, for example, the rate at which norepinephrine isadministered may be decreased by at least 15%. In other embodiments, therate at which a vasopressor (other than angiotensin II, angiotensin III,or angiotensin IV) is administered may be decreased by at least 60%. Insome embodiments, the rate at which a vasopressor (other thanangiotensin II, angiotensin III, or angiotensin IV) is administered isdecreased to 0 μg/kg/min (or μg/min, 0 U/kg/min, or 0 U/min).

A vasopressor may be titrated down while monitoring a patient's MAP, andtitration may occur over the course of minutes to hours. Thus, the rateat which a vasopressor is administered may be decreased by at least 1%,2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%,18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%,32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%,46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%,60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%,74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%,99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or more over thecourse of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105,110, 115, 120, 135, 150, 165, 180, 195, 210, 225, or 240 minutes, orover the course of about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0,8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0,14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0,20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or48 hours or longer.

The rate of administration may be titrated by administering angiotensinII (or angiotensin III or angiotensin IV) at an initial rate and thenincreasing or decreasing the rate of administration. In some cases, thepatient may be administered an initial bolus of angiotensin II (orangiotensin III or angiotensin IV) followed by the administration ofangiotensin II (or angiotensin III or angiotensin IV) at a lower rate.Alternatively, the patient may be administered angiotensin II (orangiotensin III or angiotensin IV) at a low rate followed by gradual,elevated rates. Thus, in some embodiments, the method further comprisesincreasing the rate at which angiotensin II (or angiotensin III orangiotensin IV) is administered, and in other embodiments, the methodfurther comprises decreasing the rate at which angiotensin II (orangiotensin III or angiotensin IV) is administered. For example,angiotensin II (or angiotensin III or angiotensin IV) may beadministered at an initial rate of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0,2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4,3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2,6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20 ng/kg/min, and the rate may be increased to a finalrate of about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0,6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4,7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8,8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 ng/kg/min. Alternatively,angiotensin II (or angiotensin III or angiotensin IV) may beadministered at an initial rate of about 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, or 60 ng/kg/min, and the rate may be decreasedto a final rate of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9,1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3,2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7,3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1,5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5,6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9,8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3,9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or20 ng/kg/min. Angiotensin II (or angiotensin III or angiotensin IV) maybe titrated while monitoring a patient's MAP, and titration may occurover the course of minutes to hours. Thus, the rate at which at whichangiotensin II (or angiotensin III or angiotensin IV) is administeredmay be increased or decreased over the course of 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 65, 70,75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 135, 150, 165, 180, 195,210, 225, or 240 minutes, or over the course of about 4.0, 4.5, 5.0,5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5,12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5,18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, or 48 hours or longer.

Angiotensin II (or angiotensin III or angiotensin IV) may beadministered as long as necessary to maintain a MAP above a targetvalue. Alternatively, angiotensin II (or angiotensin III or angiotensinIV) may be administered until the patient's MAP can be maintained at alower dose of a vasopressor other than angiotensin II (or angiotensinIII or angiotensin IV). In some embodiments, the composition isadministered until the mean arterial pressure of the patient can bemaintained at or above 70 mm Hg with less than 0.1 μg/kg/minnorepinephrine, less than 0.1 μg/kg/min epinephrine, less than 15μg/kg/min dopamine, or less than 0.01 U/min vasopressin. In otherembodiments, the composition is administered continuously over a periodof time selected from less than 6 hours; from 6 hours to 24 hours; or atleast 24 hours. In other embodiments, the composition is administeredcontinuously for at least 1-6 days, such as 1-11 days.

The methods disclosed herein can use any suitable form or analog ofangiotensin II that exhibits the desired effect of increasing MAP inhuman subjects. In some embodiments, the angiotensin II has the sequenceset forth in SEQ ID NO:1,l SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ IDNO:5, SEQ ID NO:6, SEQ ID NO:7, or SEQ ID NO:8. Preferably, theangiotensin II has the sequence set forth in SEQ ID NO:1.

In some embodiments, the angiotensin II is selected from 5-L-valineangiotensin II; 1-L-asparagine-5-L-valine angiotensin II;1-L-asparagine-5-L-isoleucine angiotensin II; or 1-L-asparagine-5-L-isoleucine angiotensin II, preferably 5-L-isoleucine angiotensin II.The angiotensin II may be formulated as a pharmaceutically acceptablesalt, for example, as an acetate salt.

The methods disclosed herein can use any suitable form or analog ofangiotensin III that exhibits the desired effect of increasing MAP inhuman subjects. In some embodiments, the angiotensin III has thesequence set forth in SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ IDNO:12, or SEQ ID NO:13. Preferably, the angiotensin III has the sequenceset forth in SEQ ID NO:9.

In some embodiments, the angiotensin III is selected from 4-L-valineangiotensin III or 4-L-isoleucine angiotensin III, preferably4-L-isoleucine angiotensin III. The angiotensin III may be formulated asa pharmaceutically acceptable salt, for example, as an acetate salt.

The methods disclosed herein can use any suitable form or analog ofangiotensin IV that exhibits the desired effect of increasing MAP inhuman subjects. In some embodiments, the angiotensin IV has the sequenceset forth in SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, orSEQ ID NO:18. Preferably, the angiotensin IV has the sequence set forthin SEQ ID NO:14.

In some embodiments, the angiotensin IV is selected from 3-L-valineangiotensin III or 3-L-isoleucine angiotensin IV, preferably3-L-isoleucine angiotensin IV. The angiotensin IV may be formulated as apharmaceutically acceptable salt, for example, as an acetate salt.

The composition may be formulated with varying concentrations ofangiotensin II. Thus, in certain embodiments, the composition comprisesangiotensin II at a concentration of about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 15, 20, 25, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220,230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360,370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500,550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 μg/ml. In otherembodiments, the composition comprises angiotensin II at a concentrationof about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2,2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7,3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2,5.3, 5.4, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0,11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0,17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0,23.5, 24.0, 24.5, or 25.0 mg/ml. Thus, in certain embodiments, thecomposition comprises angiotensin II at a concentration of about 2.5mg/mL. The composition may comprise 0 mg/mL angiotensin II when thecomposition comprises angiotensin III and/or angiotensin IV.

The composition may be formulated with varying concentrations ofangiotensin III. Thus, in certain embodiments, the composition comprisesangiotensin III at a concentration of about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 15, 20, 25, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220,230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360,370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500,550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 μg/ml. In otherembodiments, the composition comprises angiotensin III at aconcentration of about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4,3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9,5, 5.1, 5.2, 5.3, 5.4, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5,10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5,16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5,22.0, 22.5, 23.0, 23.5, 24.0, 24.5, or 25.0 mg/ml. Thus, in certainembodiments, the composition comprises angiotensin III at aconcentration of about 5 mg/mL. The composition may comprise 0 mg/mLangiotensin III when the composition comprises angiotensin II and/orangiotensin IV.

The composition may be formulated with varying concentrations ofangiotensin IV. Thus, in certain embodiments, the composition comprisesangiotensin IV at a concentration of about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 15, 20, 25, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220,230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360,370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500,550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 μg/ml. In otherembodiments, the composition comprises angiotensin IV at a concentrationof about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2,2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7,3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2,5.3, 5.4, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0,11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0,17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0,23.5, 24.0, 24.5, or 25.0 mg/ml. Thus, in certain embodiments, thecomposition comprises angiotensin IV at a concentration of about 5mg/mL. The composition may comprise 0 mg/mL angiotensin IV when thecomposition comprises angiotensin II and/or angiotensin III.

In certain embodiments, the composition comprises an excipient, such asmannitol.

In certain embodiments, the composition is suitable for parenteraladministration, such as injection or intravenous infusion, preferablyintravenous infusion.

In some embodiments, the patient has sepsis. The patient may have septicshock, distributive shock, or cardiogenic shock.

In some embodiments, the patient is a mammal, such as a primate, ovine,porcine, canine, or rodent, preferably a human.

The rate of administration of the angiotensin II (or angiotensin III orangiotensin IV) can be modulated manually and/or automatically inresponse to measurements of the patient's mean arterial pressureobtained periodically or sporadically during treatment, e.g., tomaintain a mean arterial pressure at this level, or within apredetermined range (e.g., 80-110 mm Hg).

In certain embodiments, the invention provides a method of assessing theresponse of a patient (such as a human) with hypotension to angiotensinII, angiotensin III, or angiotensin IV therapy, comprising administeringto the patient an initial dose of a composition comprising angiotensinII, angiotensin III, or angiotensin IV (which may be a therapeutic doseor a sub-therapeutic dose, for example, a dose less than 1 ng/kg/min orabout 1 ng/kg/min) and testing the patient for a change in a therapeuticparameter (e.g., blood pressure). For example, the therapeutic parameterof the patient can be assessed prior to administering the initial doseand again after administering the initial dose (e.g., at least half anhour later, preferably at least one hour later and/or up to 8 hourslater, preferably up to 6 hours later, such as between 1 and 6 hoursafter administering the initial dose). Comparing the assessment of thetherapeutic parameter after administering the initial dose to theassessment made prior to administering the initial dose will indicatewhether the parameter is increasing or decreasing as a result of theangiotensin II, angiotensin III, or angiotensin IV therapy. Typically,an increase in the patient's blood pressure is indicative of a positiveresponse to the angiotensin II, angiotensin III, and/or angiotensin IVtherapy. In certain embodiments, where the patient exhibits a positiveresponse to the therapy, the method further comprises administering anadditional dose of angiotensin II, angiotensin III, or angiotensin IV tothe patient. If a patient exhibits a negative response (e.g., a decreasein the patient's blood pressure), the patient will typically receive noadditional doses of angiotensin II, angiotensin III, or angiotensin IV.If a patient exhibits no response or an insignificant response, themethod may further comprise administering a higher dose of thecomposition than the initial dose and further testing the patient for aresponse to the higher dose. Alternatively, if the patient exhibits noresponse or an insignificant response, the patient may receive nofurther doses of angiotensin II, angiotensin III, or angiotensin IVtherapy.

Angiotensin Therapeutics

Angiotensin II, angiotensin III, and angiotensin IV are peptide hormonesnaturally produced by the body that regulates blood pressure viavasoconstriction and sodium reabsorption. Hemodynamic effects ofangiotensin II administration have been the patient of numerous clinicalstudies, demonstrating significant effects on systemic and renal bloodflow (Harrison-Bernard, L. M., The renal renin-angiotensin system. AdvPhysiol Educ, 33(4):270 (2009)). Angiotensin II is a hormone produced bythe renin angiotensin aldosterone system (RAAS) that modulates bloodpressure via regulation of vascular smooth muscle tone and extracellularfluid homeostasis. Angiotensin II mediates its effects on thevasculature by inducing vasoconstriction and sodium retention, and so isthe target of many therapies for hypertension. In addition to itssystemic effects, angiotensin II has a pronounced effect on the efferentarterioles of the kidney, maintaining glomerular filtration when bloodflow is decreased. Angiotensin II also regulates sodium reabsorption inthe kidney by stimulating Na+/H+exchangers in the proximal tubule andinducing the release of aldosterone and vasopressin (Harrison-Bernard,L. M., The renal renin-angiotensin system. Adv Physiol Educ, 33(4):270(2009)).

The angiotensin II therapeutic that may be used for in the compositionsand methods of this disclosure may be Asp-Arg-Val-Tyr-Ile-His-Pro-Phe(SEQ ID NO: 1) also called 5-isoleucine angiotensin II. SEQ ID NO: 1 isan octa-peptide naturally present in humans and other species, such asequines, hogs, etc. Isoleucine may be substituted by valine to result in5-valine angiotensin II, Asp-Arg-Val-Tyr-Val-His-Pro-Phe (SEQ ID NO: 2).Other angiotensin II analogues such as [Asn¹-Phe⁴]-angiotensin II (SEQID NO: 3), hexapeptide Val-Tyr-Ile-His-Pro-Phe (SEQ ID NO: 4),nonapeptide Asn-Arg-Val-Tyr-Tyr-Val-His-Pro-Phe (SEQ ID NO: 5),[Asn¹-Ile⁵-Ile⁸]-angiotensin II (SEQ ID NO: 6),[Asn¹-Ile⁵-Ala⁸]-angiotensin II (SEQ ID NO: 7), and[Asn¹-diiodoTyr⁴-Ile⁵]-angiotensin II (SEQ ID NO: 8) may also be used.Angiotensin II may be synthesized, for example, by solid phase peptidesynthesis to incorporate modifications, such as C-terminal amidation.The term “angiotensin II”, without further specificity, is intended torefer to any of these various forms, as well as combinations thereof.

In some aspects, a composition comprising angiotensin II may be selectedfrom 5-valine angiotensin II, 5-valine angiotensin II amide,5-L-isoleucine angiotensin II, and 5-L-isoleucine angiotensin II amide,or a pharmaceutically acceptable salt thereof, preferably manufacturedunder current good manufacturing conditions (cGMP). In some aspects, thecomposition may include different forms of angiotensin II in differentpercentages, e.g., a mixture of hexapeptide and nonapeptide angiotensin.The composition comprising angiotensin II may be suitable for parenteraladministration, e.g., for injection or intravenous infusion.

The sequence of angiotensin II used in the compositions and methodsdisclosed herein may be homologous to the sequences of angiotensin IIdescribed above. In certain aspects, the invention includes isolated,synthetic, or recombinant amino acid sequences that are at least 80%,85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 1, 2, 3, 4,5, 6, 7, and/or 8. Any such variant sequences may be used in place of anangiotensin II as described in the preceding paragraph.

Angiotensin III is a metabolite of angiotensin II with approximately 40%of the activity of angiotensin II. An angiotensin III therapeutic thatmay be used for in the compositions and methods of this disclosure maybe Arg-Val-Tyr-Ile-His-Pro-Phe (SEQ ID NO: 9). SEQ ID NO: 9 is anhepta-peptide naturally present in humans and other species, such asequines, hogs, etc. Isoleucine may be substituted by valine to result inArg-Val-Tyr-Val-His-Pro-Phe (SEQ ID NO: 10). Other angiotensin IIIanalogues such as [Phe³]-angiotensin III (SEQ ID NO: 11),[Ile³-Ala⁷]-angiotensin III (SEQ ID NO: 12), and[diiodoTyr³-Ile⁴]-angiotensin III (SEQ ID NO: 13) may also be used.Angiotensin III may be synthesized, for example, by solid phase peptidesynthesis to incorporate modifications, such as C-terminal amidation.The term “angiotensin III”, without further specificity, is intended torefer to any of these various forms, as well as combinations thereof.

In some aspects, a composition comprising angiotensin III may beselected from 4-valine angiotensin III, 4-valine angiotensin III amide,4-L-isoleucine angiotensin III, and 4-L-isoleucine angiotensin IIIamide, or a pharmaceutically acceptable salt thereof, preferablymanufactured under current good manufacturing conditions (cGMP). Acomposition comprising angiotensin III may be suitable for parenteraladministration, e.g., for injection or intravenous infusion.

Angiotensin IV is a metabolite of angiotensin III with less activitythan angiotensin II. An angiotensin IV therapeutic that may be used forin the compositions and methods of this disclosure may beVal-Tyr-Ile-His-Pro-Phe (SEQ ID NO: 14). SEQ ID NO: 14 is anhexa-peptide naturally present in humans and other species, such asequines, hogs, etc. Isoleucine may be substituted by valine to result inVal-Tyr-Val-His-Pro-Phe (SEQ ID NO: 15). Other angiotensin IV analoguessuch as [Phe²]-angiotensin IV (SEQ ID NO: 16), [Ile³-Ala⁶]-angiotensinIV (SEQ ID NO: 17), and [diiodoTyr²-Ile³]-angiotensin IV (SEQ ID NO: 18)may also be used. Angiotensin IV may be synthesized, for example, bysolid phase peptide synthesis to incorporate modifications, such asC-terminal amidation. The term “angiotensin IV”, without furtherspecificity, is intended to refer to any of these various forms, as wellas combinations thereof.

In some aspects, a composition comprising angiotensin IV may be selectedfrom 3-valine angiotensin IV, 3-valine angiotensin IV amide,3-L-isoleucine angiotensin IV, and 3-L-isoleucine angiotensin IV amide,or a pharmaceutically acceptable salt thereof, preferably manufacturedunder current good manufacturing conditions (cGMP). A compositioncomprising angiotensin IV may be suitable for parenteral administration,e.g., for injection or intravenous infusion.

An angiotensin II, angiotensin III, or angiotensin IV therapeutic may beused as any suitable salt, deprotected form, acetylated form,deacetylated form, and/or prodrug form of the above-mentioned peptides,including pegylated forms of the peptides or conjugates as disclosed inUS Patent Publication 2011/0081371 (incorporated by reference). The term“prodrug” refers to any precursor compound which is able to generate orto release the above-mentioned peptide under physiological conditions.Such prodrugs may be larger peptides which are selectively cleaved inorder to form the peptide of the invention. For example, in someaspects, the prodrug may be angiotensinogen, angiotensin I, or itshomologues that may result in angiotensin II by the action of certainendogenous or exogenous enzymes. Further prodrugs include peptides withprotected amino acids, e.g., having protecting groups at one or morecarboxylic acid and/or amino groups. Suitable protecting groups foramino groups include the benzyloxycarbonyl, t-butyloxycarbonyl (BOC),fluorenylmethyloxycarbonyl (FMOC), formyl, and acetyl or acyl group.Suitable protecting groups for the carboxylic acid group include esterssuch as benzyl esters or t-butyl esters. The present invention alsocontemplates the use of angiotensin II, angiotensin III, angiotensin IVand/or precursor peptides having amino acid substitutions, deletions,additions, the substitutions and additions including the standard D andL amino acids and modified amino acids, such as, for example, amidatedand acetylated amino acids, wherein the therapeutic activity of the basepeptide sequence is maintained at a pharmacologically useful level.

Doses of the Therapeutically Effective Substance

In general, angiotensin II, angiotensin III, and angiotensin IV increaseblood pressure, and patients who are hypotensive may require largerdoses to exhibit pressor responses similar to those observed in normalpatients. The composition including the angiotensin therapeutic (e.g.,angiotensin II, angiotensin III, or angiotensin IV) can be administeredat a rate sufficient to achieve an increase in blood pressure of atleast about 10-15 mm Hg and optionally for at least angiotensintherapeutic administered may be varied in response to changes in otherphysiological parameters such as renal vascular resistance, renal bloodflow, filtration fractions, mean arterial pressure, etc. For example,the rate of administration of the angiotensin therapeutic may start fromabout 2 ng/kg/min to about 20 ng/kg/min and is increased based on themean arterial pressure (“MAP”). In some aspects, the rate ofadministration may be increased such that the MAP does not exceed about70 mm Hg, about 80 mm Hg, about 90 mm Hg, about 100 mm Hg, about 110 mmHg, etc. For example, a patient may be coupled to a monitor thatprovides continuous, periodic, or occasional measurements of MAP duringsome or all of the course of treatment. The rate of administration maybe modulated manually (e.g., by a physician or nurse) or automatically(e.g., by a medical device capable of modulating delivery of thecomposition in response to MAP values received from the monitor) tomaintain the patient's MAP within a desired range (e.g., 80-110 mm Hg)or below a desired threshold, e.g., as set forth above.

The composition including the angiotensin therapeutic may beadministered over a period of time selected from at least 8 hours; atleast 24 hours; and from 8 hours to 24 hours. The composition includingthe angiotensin therapeutic may be administered continuously for atleast 2-6 days, such as 2-11 days, continuously for 2-6 days, for 8hours a day over a period of at least 2-6 days, such as 2-11 days. Aweaning period (from several hours to several days) may be beneficialafter prolonged infusion.

The composition including the angiotensin therapeutic may furtherinclude one or more additional pharmaceutical agent. For example,angiotensin II, angiotensin III, or angiotensin IV may be administeredwith albumin. The quantity of the additional pharmaceutical agentadministered may vary depending on the cumulative therapeutic effect ofthe treatment including the angiotensin therapeutic and the additionalpharmaceutical agent. For example, the quantity of albumin administeredmay be 1 gram of albumin per kilogram of body weight given intravenouslyon the first day, followed by 20 to 40 grams daily. Yet other additionalpharmaceutical agents may be any one or more of midodrine, octreotide,somatostatin, vasopressin analogue ornipressin, terlipressin,pentoxifylline, acetylcysteine, norepinephrine, misoprostol, etc. Insome aspects, other natriuretic peptides may also be used in combinationwith the angiotensin therapeutic to remedy the impairment of sodiumexcretion associated with diseases discussed above. For example,natriuretic peptides may include any type of atrial natriuretic peptide(ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide(CNP), and/or dendroaspis natriuretic peptide, etc. Several diureticcompounds may be used in combination with the angiotensin therapeutic toinduce urine output. For example any one or more of the xanthines suchas caffeine, theophylline, theobromine; thiazides such asbendroflumethiazide, hydrochlorothiazide; potassium-sparing diureticssuch as amiloride, spironolactone, triamterene, potassium canrenoate;osmotic diuretics such as glucose (especially in uncontrolled diabetes),mannitol; loop diuretics such as bumetanide, ethacrynic acid,furosemide, torsemide; carbonic anhydrase inhibitors such asacetazolamide, dorzolamide; Na-H exchanger antagonists such as dopamine;aquaretics such as goldenrod, juniper; arginine vasopressin receptor 2antagonists such as amphotericin B, lithium citrate; acidifying saltssuch as CaCl₂, NH₄Cl; ethanol, water, etc. may be used in combinationwith the angiotensin therapeutic to treat the patient. The list ofadditional pharmaceutical agents described above is merely illustrativeand may include any other pharmaceutical agents that may be useful forthe treatment of hypotension and related conditions.

Excipients

The pharmaceutical compositions of the present invention may alsocontain diluents, fillers, salts, buffers, stabilizers, solubilizers,and other materials well known in the art. The term “pharmaceuticallyacceptable carrier” refers to a non-toxic carrier that may beadministered to a patient, together with a therapeutically effectivesubstance (such as angiotensin II) of this invention, and which does notdestroy the pharmacological activity of the therapeutically effectivesubstance. The term “pharmaceutically acceptable” means a non-toxicmaterial that does not interfere with the effectiveness of thebiological activity of the active ingredient(s). The characteristics ofthe carrier will depend on the route of administration. The term“excipient” refers to an additive in a formulation or composition thatis not a pharmaceutically active ingredient.

One of skill in the art would appreciate that the choice of any oneexcipient may influence the choice of any other excipient. For example,the choice of a particular excipient may preclude the use of one or moreadditional excipients because the combination of excipients wouldproduce undesirable effects. One of skill in the art would be able toempirically determine which excipients, if any, to include in thecompositions of the invention. Excipients of the invention may include,but are not limited to, co-solvents, solubilizing agents, buffers, pHadjusting agents, bulking agents, surfactants, encapsulating agents,tonicity-adjusting agents, stabilizing agents, protectants, andviscosity modifiers. In some aspects, it may be beneficial to include apharmaceutically acceptable carrier in the compositions of theinvention.

Solubilizing Agents

In some aspects, it may be beneficial to include a solubilizing agent inthe compositions of the invention. Solubilizing agents may be useful forincreasing the solubility of any of the components of the formulation orcomposition, including a therapeutically effective substance (e.g.,angiotensin II, angiotensin III, or angiotensin IV) or an excipient. Thesolubilizing agents described herein are not intended to constitute anexhaustive list, but are provided merely as exemplary solubilizingagents that may be used in the compositions of the invention. In certainaspects, solubilizing agents include, but are not limited to, ethylalcohol, tert-butyl alcohol, polyethylene glycol, glycerol,methylparaben, propylparaben, polyethylene glycol, polyvinylpyrrolidone, and any pharmaceutically acceptable salts and/orcombinations thereof.

pH-adjusting Agents

In some aspects, it may be beneficial to adjust the pH of thecompositions by including a pH-adjusting agent in the compositions ofthe invention. Modifying the pH of a formulation or composition may havebeneficial effects on, for example, the stability or solubility of atherapeutically effective substance, or may be useful in making aformulation or composition suitable for parenteral administration.pH-adjusting agents are well known in the art. Accordingly, thepH-adjusting agents described herein are not intended to constitute anexhaustive list, but are provided merely as exemplary pH-adjustingagents that may be used in the compositions of the invention.pH-adjusting agents may include, for example, acids and bases. In someaspects, a pH-adjusting agent includes, but is not limited to, aceticacid, hydrochloric acid, phosphoric acid, sodium hydroxide, sodiumcarbonate, and combinations thereof.

The pH of the compositions of the invention may be any pH that providesdesirable properties for the formulation or composition. Desirableproperties may include, for example, therapeutically effective substance(e.g., angiotensin II, angiotensin III, or angiotensin IV) stability,increased therapeutically effective substance retention as compared tocompositions at other pHs, and improved filtration efficiency. In someaspects, the pH of the compositions of the invention may be from about3.0 to about 9.0, e.g., from about 5.0 to about 7.0. In particularaspects, the pH of the compositions of the invention may be 5.5±0.1,5.6±0.1, 5.7±0.1, 5.8±0.1, 5.9±0.1, 6.0±0.1, 6.1±0.1, 6.2±0.1, 6.3±0.1,6.4±0.1, or 6.5±0.1.

Buffers

In some aspects, it may be beneficial to buffer the pH by including oneor more buffers in the compositions. In certain aspects, a buffer mayhave a pKa of, for example, about 5.5, about 6.0, or about 6.5. One ofskill in the art would appreciate that an appropriate buffer may bechosen for inclusion in compositions of the invention based on its pKaand other properties. Buffers are well known in the art. Accordingly,the buffers described herein are not intended to constitute anexhaustive list, but are provided merely as exemplary buffers that maybe used in the compositions of the invention. In certain aspects, abuffer may include one or more of the following: Tris, Tris HCl,potassium phosphate, sodium phosphate, sodium citrate, sodium ascorbate,combinations of sodium and potassium phosphate, Tris/Tris HCl, sodiumbicarbonate, arginine phosphate, arginine hydrochloride, histidinehydrochloride, cacodylate, succinate, 2-(N-morpholino)ethanesulfonicacid (MES), maleate, bis-tris, phosphate, carbonate, and anypharmaceutically acceptable salts and/or combinations thereof.

Surfactants

In some aspects, it may be beneficial to include a surfactant in thecompositions of the invention. Surfactants, in general, decrease thesurface tension of a liquid composition. This may provide beneficialproperties such as improved ease of filtration. Surfactants also may actas emulsifying agents and/or solubilizing agents. Surfactants are wellknown in the art. Accordingly, the surfactants described herein are notintended to constitute an exhaustive list, but are provided merely asexemplary surfactants that may be used in the compositions of theinvention. Surfactants that may be included include, but are not limitedto, sorbitan esters such as polysorbates (e.g., polysorbate 20 andpolysorbate 80), lipopolysaccharides, polyethylene glycols (e.g., PEG400 and PEG 3000), poloxamers (i.e., pluronics), ethylene oxides andpolyethylene oxides (e.g., Triton X-100), saponins, phospholipids (e.g.,lecithin), and combinations thereof.

Tonicity-adjusting Agents

In some aspects, it may be beneficial to include a tonicity-adjustingagent in the compositions of the invention. The tonicity of a liquidcomposition is an important consideration when administering thecomposition to a patient, for example, by parenteral administration.Tonicity-adjusting agents, thus, may be used to help make a formulationor composition suitable for administration. Tonicity-adjusting agentsare well known in the art. Accordingly, the tonicity-adjusting agentsdescribed herein are not intended to constitute an exhaustive list, butare provided merely as exemplary tonicity-adjusting agents that may beused in the compositions of the invention. Tonicity-adjusting agents maybe ionic or non-ionic and include, but are not limited to, inorganicsalts, amino acids, carbohydrates, sugars, sugar alcohols, andcarbohydrates. Exemplary inorganic salts may include sodium chloride,potassium chloride, sodium sulfate, and potassium sulfate. An exemplaryamino acid is glycine. Exemplary sugars may include sugar alcohols suchas glycerol, propylene glycol, glucose, sucrose, lactose, and mannitol.

Stabilizing Agents

In some aspects, it may be beneficial to include a stabilizing agent inthe compositions of the invention. Stabilizing agents help increase thestability of a therapeutically effective substance in compositions ofthe invention. This may occur by, for example, reducing degradation orpreventing aggregation of a therapeutically effective substance. Withoutwishing to be bound by theory, mechanisms for enhancing stability mayinclude sequestration of the therapeutically effective substance from asolvent or inhibiting free radical oxidation of the anthracyclinecompound. Stabilizing agents are well known in the art. Accordingly, thestabilizing agents described herein are not intended to constitute anexhaustive list, but are provided merely as exemplary stabilizing agentsthat may be used in the compositions of the invention. Stabilizingagents may include, but are not limited to, emulsifiers and surfactants.

Routes of Delivery

The compositions of the invention can be administered in a variety ofconventional ways. In some aspects, the compositions of the inventionare suitable for parenteral administration. These compositions may beadministered, for example, intraperitoneally, intravenously,intrarenally, or intrathecally. In some aspects, the compositions of theinvention are injected intravenously. One of skill in the art wouldappreciate that a method of administering a therapeutically effectivesubstance formulation or composition of the invention would depend onfactors such as the age, weight, and physical condition of the patientbeing treated, and the disease or condition being treated. The skilledworker would, thus, be able to select a method of administration optimalfor a patient on a case-by-case basis.

Unless otherwise defined herein, scientific and technical terms used inthis application shall have the meanings that are commonly understood bythose of ordinary skill in the art. Generally, nomenclature andtechniques relating to chemistry, molecular biology, cell and cancerbiology, immunology, microbiology, pharmacology, and protein and nucleicacid chemistry, described herein, are those well-known and commonly usedin the art.

Throughout this specification, the word “comprise” or variations such as“comprises” or “comprising” will be understood to imply the inclusion ofa stated integer (or components) or group of integers (or components),but not the exclusion of any other integer (or components) or group ofintegers (or components). The singular forms “a,” “an,” and “the”include the plurals unless the context clearly dictates otherwise. Theterm “including” is used to mean “including but not limited to.”“Including” and “including but not limited to” are used interchangeably.The terms “patient” and “individual” are used interchangeably and referto either a human or a non-human animal. These terms include mammalssuch as humans, primates, livestock animals (e.g., bovines, porcines),companion animals (e.g., canines, felines) and rodents (e.g., mice,rabbits and rats).

“About” and “approximately” shall generally mean an acceptable degree oferror for the quantity measured given the nature or precision of themeasurements. Typically, exemplary degrees of error are within 20%,preferably within 10%, and more preferably within 5% of a given value orrange of values. Alternatively, and particularly in biological systems,the terms “about” and “approximately” may mean values that are within anorder of magnitude, preferably within 5-fold and more preferably within2-fold of a given value. Numerical quantities given herein areapproximate unless stated otherwise, meaning that the term “about” or“approximately” can be inferred when not expressly stated.

Incorporation by Reference

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference. In case of conflict, the present specification, including itsspecific definitions, will control. While specific aspects of thepatient matter have been discussed, the above specification isillustrative and not restrictive. Many variations will become apparentto those skilled in the art upon review of this specification and theclaims below. The full scope of the invention should be determined byreference to the claims, along with their full scope of equivalents, andthe specification, along with such variations.

What is claimed is:
 1. A method of treating hypotension in a humanpatient, comprising: measuring a ratio of blood concentration ofangiotensin I to blood concentration of angiotensin II in the patient;and administering to the patient a composition comprising angiotensinII.
 2. The method of claim 1, wherein the method comprises administeringangiotensin II at an initial rate of less than 10 ng/kg/min if the ratioof angiotensin I to angiotensin II is at least 1:1.
 3. The method ofclaim 1, comprising administering angiotensin II at an initial rate ofgreater than or equal to 10 ng/kg/min if the ratio of angiotensin I toangiotensin II is less than 1:1.
 4. The method of claim 1, wherein thepatient has acute respiratory distress syndrome.
 5. The method of claim1, wherein the patient has an initial mean arterial pressure of 75 mm Hgor less prior to administering the composition.
 6. The method of claim1, further comprising: measuring a mean atrial blood pressure of thepatient; and increasing the rate of administering angiotensin II if themean arterial blood pressure is less than 75 mm Hg.
 7. The method ofclaim 1, wherein the composition comprises 5-L-valine angiotensin II;1-L-asparagine-5-L-valine angiotensin II; 1-L-asparagine-5-L-isoleucineangiotensin II; or 5-L-isoleucine angiotensin II.
 8. The method of claim1, wherein administering the composition comprises administering thecomposition by injection or intravenous infusion.
 9. The method of claim1, wherein the patient has a cardiovascular sequential organ failureassessment score (“SOFA score”) of 3 or 4 prior to administering thecomposition.
 10. The method of claim 1, wherein the patient has sepsis,septic shock, distributive shock, or cardiogenic shock.
 11. The methodof claim 1, wherein the method comprises administering angiotensin II atan initial rate of less than 5 ng/kg/min if the ratio of angiotensin Ito angiotensin II is at least 1:1.
 12. The method of claim 1, comprisingadministering angiotensin II at an initial rate of greater than or equalto 5 ng/kg/min if the ratio of angiotensin I to angiotensin II is lessthan 1:1.
 13. A method of treating hypotension in a human patientreceiving a vasopressor and having an initial mean arterial pressure,comprising: measuring a ratio of angiotensin I to angiotensin II;administering to the patient a composition comprising angiotensin II inthe patient; after a subsequent period of time, measuring the meanarterial pressure of the patient; and if the measured mean arterialpressure is at or above 75 mm Hg, decreasing the rate at which thevasopressor is administered to the patient.
 14. The method of claim 13,wherein the method comprises administering angiotensin II at an initialrate of less than 20 ng/kg/min if the ratio of angiotensin I toangiotensin II is at least 1:1.
 15. The method of claim 13, comprisingadministering angiotensin II at an initial rate of greater than or equalto 20 ng/kg/min if the ratio of angiotensin I to angiotensin II is lessthan 1:1.
 16. A method of treating hypotension in a human patientreceiving a vasopressor and having an initial mean arterial pressure,comprising: measuring a ratio of blood concentration of angiotensin I toblood concentration of angiotensin II in the patient; administering tothe patient a composition comprising angiotensin II; after a subsequentperiod of time, measuring the mean arterial pressure of the patient; andif the measured mean arterial pressure is at least 10 mm Hg higher thanthe initial mean arterial pressure, decreasing the rate at which thevasopressor is administered to the patient.